LRBA

LRBA is a large BEACH-domain membrane-trafficking scaffold that cycles among cytosolic, trans-Golgi, endosomal, and other endomembrane pools. ARF-family GTPases recruit LRBA to the trans-Golgi network and Rab4-positive endosomes, where it supports endosomal traffic and endolysosome homeostasis. In activated and regulatory human T cells, LRBA routes the inhibitory receptor CTLA4 toward Rab11 recycling compartments and away from lysosomal degradation, thereby maintaining CTLA4 abundance and immune homeostasis. LRBA also participates in ATG9A-vesicle delivery to damaged mitochondria during phagophore growth and PINK1/Parkin mitophagy. In activated human B cells, LRBA binds the regulatory RIIalpha and RIIbeta subunits of protein kinase A and can act as an activation-dependent A-kinase anchoring protein. Biallelic LRBA loss causes an immunodeficiency and autoimmunity syndrome with impaired B-cell activation, plasmablast formation, immunoglobulin secretion, and CTLA4-dependent immune regulation. The LRBA PH-BEACH tandem forms an integrated structural unit, but its PH domain did not bind phospholipids in direct assays. Two reviewed protein isoforms exist, without evidence that the established trafficking or anchoring functions are isoform-specific.

Disorders

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